5,2′-Dibromo-2,4′,5′-trihydroxydiphenylmethanone Inhibits LPS-Induced Vascular Inflammation by Targeting the Cav1 Protein

Abstract

Vascular inflammation is directly responsible for atherosclerosis. 5,2′-Dibromo-2,4′,5′-trihydroxydiphenylmethanone (TDD), a synthetic bromophenol derivative, exhibits anti-atherosclerosis and anti-inflammatory effects. However, the underlying pathways are not yet clear. In this study, we first examined the effects of TDD on toll-like receptor-4 (TLR4) activity, the signaling receptor for lipopolysaccharide (LPS), and found that TDD does not inhibit LPS-induced TLR4 expression in EA.hy926 cells and the vascular wall in vivo. Next, we investigated the global protein alterations and the mechanisms underlying the action of TDD in LPS-treated EA.hy926 cells using an isobaric tag for the relative and absolute quantification technique. Western blot analysis revealed that TDD inhibited NF-κB activation by regulating the phosphorylation and subsequent degradation IκBα. Among the differentially expressed proteins, TDD concentration-dependently inhibited Caveolin 1(Cav1) expression. The interaction between Cav1 and TDD was determined by using biolayer interference assay, UV-vis absorption spectra, fluorescence spectrum, and molecular docking. We found that TDD can directly bind to Cav1 through hydrogen bonds and van der Waals forces. In conclusion, our results showed that TDD inhibited LPS-induced vascular inflammation and the NF-κB signaling pathway by specifically targeting the Cav1 protein. TDD may be a novel anti-inflammatory compound, especially for the treatment of atherosclerosis.

Caveolin-1 in endothelial cells: A potential therapeutic target for atherosclerosis

“…It assessedits non-carcinogenicity [ 139 ], suggesting that Cav1 has clinical translational potential. Furthermore, a number of drugs that exert anti-AS effects, such as 5,2'-Dibromo-2,4',5'-trihydroxydiphenylmethanone (TDD), exert anti-inflammatory effects precisely by specifically targeting Cav1 and thereby inhibiting LPS-induced vascular inflammation and NF-κB signaling pathways [ 138 ]. At the same time, Tiaopi Huxin recipe (TPHXR) may improve endothelium-dependent vasodilation and attenuate vascular system inflammation by increasing eNOS phosphorylation and NO levels in ApoE −/− mice through downregulation of Cav1 expression [ 140 ].…”

Recent progresses in gut microbiome mediates obstructive sleep apnea‐induced cardiovascular diseases

“…Many clinical studies have reported a positive association between levels of inflammatory markers and blood pressure 79 . Yuan et al 80 demonstrated that LPS treatment of EA.hy926 cells resulted in higher levels of IκB and NF‐κB phosphorylation compared to the control group. Additionally, LPS treatment raised the levels of typical inflammatory cytokines, interleukin 6 (IL‐6), and tumor necrosis factor‐alpha (TNF‐α), in EA.hy926 cells.…”